MeCP2倍增上调雄激素代谢致神经发育异常的机制研究

Autism spectrum disorder (ASD) is a severe neurodevelopment disorder. The etiology of ASD is unclear and currently there is no effective therapeutic drug for ASD. ASD shows a much higher frequency in male individuals, at 4:1 and even 6:1. The biological mechanisms responsible for this inequality might include risk/protection factors linked to sex-specific hormone. Duplication of MECP2(methyl-CpG binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), most MDS patients and mouse shows ASD-related traits and MDS mouse are classical animal models for ASD. Prior work has shown that neurogenesis is enhanced in MDS mouse fetal brain (CDD 2018). We have found that the androgen level of MDS male mouse were significantly higher than that of wild-type male mouse, and some of the steroidogenic enzymes involved in androgen synthesis were abnormally expressed. Additionally, there have been reports of elevated androgen in ASD. We suggest that neural developmental abnormalities caused by androgen elevation may be the biological basis of gender differences in ASD. Therefore, we will focus on the effects of androgen on regulatory mechanism of androgen levels on neural developmental abnormalities and susceptibility to ASD. We will use genetic, molecular and cellular approaches in both in vitro and in vivo studies to address this question and will also test the therapeutic potential of the prenatal sex hormone treatment. This project will provide new insight into the molecular mechanism of ASD and might highlight a potential therapeutic strategy for ASD.

自闭症是严重神经发育疾病，解析神经生物学机制对于早期诊治意义重大。自闭症患病率有显著性别差异。性激素代谢异常或可作为研究自闭症发生机制的一个新的突破口。MECP2基因编码甲基化DNA结合蛋白，与自闭症密切相关，MECP2倍增体（MDS）患者多为男性且有严重自闭症，MDS小鼠也是自闭症模型。我们前期研究发现MDS小鼠有神经干细胞分化障碍（CDD 2018）。我们近期发现MDS雄鼠的雄激素水平明显高于野生型雄鼠，且部分雄激素代谢酶也存在异常表达。结合自闭症患者在胎儿时期雄激素水平高的现象，我们提出：雄激素升高导致的神经发育异常可能是自闭症性别差异的生物学基础。本项目拟利用MDS小鼠和孕鼠高雄激素模型，研究雄激素代谢异常对雌雄鼠大脑皮层发育的作用，从分子水平到模式生物层面验证雄性激素水平对神经发育异常和自闭症易感性的调控机制。预期成果将丰富对自闭症病理机制的理解。

在大脑发育期间高雄激素可能会增加神经发育障碍的易感性，如自闭症谱系障碍和其他神经发育类疾病。然而，人们对高雄激素在大脑发育中的作用知之甚少。雄激素异常或可作为自闭症等有显著性别差异的神经发育类疾病发生机制的一个新的突破口。本项目围绕研究计划，一方面利用患者多为男性且具有高雄表型的MECP2倍增体小鼠模型(MDS)（表现严重自闭症症状），来研究其高雄症状的发生机制。发现MeCP2在参与睾酮的产生和分泌的睾丸Leydig细胞中高表达，通过上调黄体生成素受体Lhcgr促进雄激素合成并下调芳香化酶 Cyp19a1 抑制雄激素向雌激素的转化，从而提高雄激素水平。该研究结果于2021年发表于 Cell death&Disease杂志。另一方面，利用产前宫内高雄的小鼠模型来研究雄激素对后代大脑皮层发育的影响。高雄激素促进后代小鼠的皮层神经发生，该表型与自闭症模型MDS小鼠相似，并且高雄的MDS孕鼠的后代表型更严重，而雄激素拮抗剂氟他胺可以部分逆转 MDS小鼠的神经干细胞向神经元的过度分化。提示雄激素和MeCP2具有共同的调节途径。综上所述，我们的数据阐明了MECP2重复和高雄激素对皮层发育的交互作用。本项目利用MDS小鼠和孕鼠高雄激素模型 ，研究雄激素代谢异常对小鼠大脑皮层发育的作用，从分子水平到模式生物层面验证雄性激素水平对神经发育异常和自闭症易感性的调控机制。预期成果将丰富对自闭症病理机制的理解。

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